As compared with rapid release formulations, sustained release formulations release a drug continuously over an extended period of time inside the body. Thus, they can keep effective plasma level of the drug for a long time, and so reduce variance in plasma level from frequent administration of the formulation and side effects therefrom. Further, they can improve compliance from the reduced number of administration.
Various techniques are used to prepare sustained release formulations with high effectiveness and safety. Among them, the sustained release matrix tablet is known as a formulation that can be prepared in the simplest manner. Sustained release matrix tablets are frequently used in the pharmaceutical industry because they can be produced using common techniques and apparatuses. Depending on the excipient used, they are classified into water-soluble and water-insoluble matrix tablets. Water-soluble matrix tablets are of the type in which the matrix is slowly dissolved from the outside in the gastrointestinal fluid and the drug is released. Examples of such matrices include hydrophilic polymers, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), Carbopol, polyethylene oxide (POE), etc. Water-insoluble matrix tablets include ones made from waxes such as hydrogenated castor oil or synthetic resins such as ammonio methacrylate copolymer (Eudragit). The water-insoluble matrix tablets are characterized in that they have no change in appearance while the drug is slowly released over a long period of time, but the drug is released through pores from the inside of the matrix. They are advantageous over the water-soluble matrix tablets in that the drug is slowly released over a given time, which is less affected by the gastrointestinal motility.
Recently, the technique of preparing sustained release formulations using a wax is drawing a great attention. In particular, as various wax type pharmaceutical excipients are developed, a variety of techniques for preparing sustained release formulations using waxes have become available. These techniques share the common feature to use a high fusibility of the wax. Typically, various methods are used, such as melt extrusion, melt granulation, melting or dissolving a wax in an adequate solvent followed by coating the solution on the surface of particles, and dispersing a drug in a melted wax followed by compressing the dispersion into tablets.
Alternatively, a wax is not melted but employed in wet granulation or direct compression together with other excipients to manufacture tablets. However, when compressing granules or other compositions including wax into tablets, such problems as insufficient compressibility or surface adhesion may occur when they contain a high weight percentage of wax. As a result, fluidity of particles in the hopper may be remarkably decreased during tabletting, and they may severely adhere to the punch, thereby resulting in severe problems in practical manufacture. Such adhesion can be prevented to some extent by adding a lubricant, but it is usual to limit the content of a lubricant no more than 5% of the total weight of granules. This is because excessive use of the lubricant may result in capping or laminating during the tabletting. Actually, from the above-mentioned problems, the content of a wax type excipient in compositions is generally limited to below 30% when preparing tablets by wet granulation or direct compression with the wax type excipient. Therefore, only the addition of lubricant would not be sufficient to solve the adhesion of wax containing granules or other compositions in practical manufacture.
Copovidone (copolyvidone; vinylpyrrolidone-vinyl acetate (VP/VAc) copolymer; 60/40) was marketed in 1975 under the trade name of Luviskol® VA 64. In Europe and other countries, it has been utilized in the pharmaceutical industry for more than a decade. However, researches thereon and its applications in cosmetics and others have been just recently ongoing actively. At present, copovidone is marketed under the trade names of Kollidon® VA 64 (by BASF) and Plasdone S-630 (by ISP), and used as a binder, a coating agent and for sustained release formulations in the pharmaceutical industry.
Especially, it is used as a binder providing good coherence for tablets and granules, and generally used at an amount of 2-5% in granules. According to the data supplied by BASF, its copovidone has a much higher plasticity than povidone (polyvinylpyrrolidone) K-30, and thus, prevents capping during tabletting and reduces friability of manufactured tablets.
From the above properties of copovidone, it is used as a binder for direct compression of incoherent compositions.
While applicable in wet granulation, it can be also used as dissolved in water or alcohol and prepared into a binding solution, or as added to a kneading solution in a mixture with other excipients to prepare granules. Copovidone has been shown to have a low hygroscopy. When kept at RH 80% for 7 days, Kollidon® VA 64 absorbs less than 20% of water, which corresponds to less than ⅓ of Kollidon 30 (povidone K-30).
Especially, adhesion to a punch can be remarkably reduced during tabletting under a wet condition. However, in the manufacture of matrix type sustained release formulations using wax type excipients, researches on any synergic effect of copovidone and wax type excipient for the maintenance of adequate drug dissolution rate and for the prevention of adhesion of the wax to a punch and capping during tabletting have not yet been reported.
Oxycodone is an opioid analgesic that directly binds with the opioid receptor to provide analgesic effect. Since 1917, it has been clinically used for patients with moderate to severe pain. At first, oxycodone was administered by injection.
Later, as it was found that it can be absorbed rapidly even when administered orally, it began to be used as an oral solution, and then, manufactured into a rapid release tablet containing 5 mg of oxycodone. Recently, not only the US, but also many other countries including Korea adopt the Biopharmaceutics Classification System (BCS) and provide the ground of exemption from the in-vivo bioequivalence test. It is because the in-vivo behavior of a drug can be predicted from the in-vitro dissolution profile once the drug's BCS class is known. Especially, the in-vivo behavior of the drugs belonging to the BCS class I can be expected from their in-vitro profile and pharmacokinetic parameters. Oxycodone hydrochloride has a high solubility and is rapidly absorbed to the body when administered orally. Its bioavailability is 60-87% as compared to that of direct administration into bloodstream. However, AUC and Cmax increase in proportion to the administration amount within a certain range. Although oxycodone hydrochloride is not explicitly listed in the BCS class I, the drug exhibits a linear in-vivo behavior, showing the rapid absorbance at a constant rate upon dissolution, and so is considered the closet to class I of the four BCS classes.
Therefore, from such in-vivo parameters as absorption rate constant, elimination rate constant, etc. of prior injections or rapid release tablets, the drug's in-vivo behavior can be expected easily in designing its sustained release formulation. Usually, the analgesic effect of oxycodone hydrochloride sustains for 4 to 6 hours when a 5 mg rapid release tablet is administered. Clinically, it has to be usually taken 4 times a day. This causes problems for the regular medication, one of important rules in management of pains, for cancer patients. Further, too fast release of the drug associated with the administration of a rapid release tablet causes a high initial blood level and may lead to such side effects as respiratory depression, which are commonly expressed with opioid analgesics. To solve these problems, researches have been carried out on a sustained release formulation that slowly releases oxycodone and maintains an effective plasma level over an extended period of time. For example, WO 93/10765 discloses a controlled release oxycodone formulation prepared by coating the drug with an acrylic excipient for sustained release such as Eudragit to prepare granules and then coating the granules with melted stearyl alcohol. The formulation uses two kinds of excipients for sustained release and controls the drug release in two phases.
This formulation comprises 10, 20 or 40 mg of oxycodone per tablet and is marketed under the trade name of OxyContin® and instructed to be administered twice a day. This product is characterized in that it has a two-phase release profile with two different release rates during 12 hours. In addition, WO 2003/101384 discloses a sustained release formulation of oxycodone hydrochloride to be administered once per 24 hours.
This formulation for administration once a day is to improve that OxyContin® for administration twice a day provides two consecutive peaks and troughs a day. This formulation is characterized in that it includes a rapid-release part and a controlled-release part. The controlled-release part is formed by coating a double-layer tablet consisting of a drug core layer and a push layer comprising an osmotic agent, so that the drug is released slowly through a semipermeable membrane.
Then, the rapid-release composition comprising the drug of a low dose, for example, 1 mg per 20-mg tablet, is coated on the surface of the controlled-release part, and finally, such an agent as Opadry® (Colorcon, USA) is film coated thereon.
This formulation is characterized in that a 0-order dissolution pattern is attained during the drug release. This formulation shows a lag time before the drug is released from the double layers through the semipermeable membrane. The low dose rapid-release layer seems to have been introduced to prevent the retardation of drug release. As a result, it can provide the sustained drug release over 24 hours while showing a fast analgesic effect in the patient's body without delay.
However, because a lot of process parameters have to be controlled in practical production, the production efficiency is decreased. In addition, because a multi-step preparation process is required, there may be a wide range of variances in product dissolution rates, which is a frequent problem in the production of sustained release formulations.